Ferrochelatase inhibitors and methods of use

Abstract

The invention relates to a method of treatment of a patient with a ferrochelatase inhibitor, or a pharmaceutically acceptable salt thereof, or a derivative thereof. Also, the invention relates to a method of treatment of a patient with a ferrochelatase inhibitor that is a triazolopyrimidinone, or a derivative thereof, or a pharmaceutically acceptable salt thereof.

What is claimed is: 
     
         1 . A method for treating a patient with an angiogenesis-mediated disease, the method comprising administering to the patient a therapeutically effective amount of a compound, wherein the compound is a triazolopyrimidinone, or a derivative thereof, or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The method of  claim 1 , wherein the compound is of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 R 1  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, or C 6 -C 10  aryl, or C 1 -C 6  alkylNR 4 R 5 , wherein each hydrogen atom in C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, or C 6 -C 10  aryl, is independently optionally substituted with fluoro, chloro, bromo, iodo, C 1 -C 6  alkyl, —OC 1 -C 6  alkyl, or C 6 -C 10  aryl; 
 each of R 2  and R 3  is independently selected from the group consisting of H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 6 -C 10  aryl, C 1 -C 6  alkyl-C 6 -C 10  aryl, and C 1 -C 6  alkylNR 6 R 7 , provided that at least one of R 2  and R 3  is not H, wherein each hydrogen atom in C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 6 -C 10  aryl, or C 1 -C 6  alkyl-C 6 -C 10  aryl, is independently optionally substituted with fluoro, chloro, bromo, iodo, —CO 2 R 8 , C 1 -C 6  alkyl, —OC 1 -C 6  alkyl, or C 6 -C 10  aryl; or R 2  and R 3 , when taken together with the carbon atoms to which they are attached, form a 5-7 membered carbocyclic ring; 
 each of R 4 , R 5 , R 6 , or R 7  is independently selected from the group consisting of H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, 5- to 7-membered monocyclic heteroaryl, C 6 -C 10  bicyclic heteroaryl, C 6 -C 10  aryl, and C 1 -C 6  alkyl-C 6 -C 10  aryl, wherein each hydrogen atom in C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, 5- to 7-membered monocyclic heteroaryl, C 6 -C 10  bicyclic heteroaryl, C 6 -C 10  aryl, or C 1 -C 6  alkyl-C 6 -C 10  aryl is independently optionally substituted with fluoro, chloro, bromo, iodo, —CO 2 R 8 , C 1 -C 6  alkyl, —OC 1 -C 6  alkyl, —OCF 3 , —CF 3  or C 6 -C 10  aryl; and 
 R 8  is H or C 1 -C 6  alkyl. 
 
     
     
         3 . The method of  claim 2 , wherein R 1  is 4-tert-butylphenyl. 
     
     
         4 . The method of  claim 2 , wherein R 2  is C 1 -C 6  alkylNR 6 R 7 , and R 3  is H. 
     
     
         5 . The method of  claim 2 , wherein R 1  is C 1 -C 6  alkylNR 4 R 5 . 
     
     
         6 . The method of  claim 2 , wherein R 2  is n-propyl or iso-propyl, and R 3  is H. 
     
     
         7 . The method of  claim 1 , comprising administering to the patient the compound to achieve an intravitreal concentration of the compound of about 0.01 μM to about 1000 μM. 
     
     
         8 . The method of  claim 1 , wherein the angiogenesis-mediated disease is selected from the group consisting of cancer, a disease involving neovascularization, retinopathy of prematurity, wet age-related macular degeneration, hypertensive retinopathy, central retinal vein occlusion, branch retinal vein occlusion, neovascular glaucoma, retinoblastoma, diabetic macular edema, and proliferative diabetic retinopathy. 
     
     
         9 . The method of  claim 1 , further comprising administering one or more of N-methylprotoporphyrin (NMPP) or an analog thereof, griseofulvin or an analog thereof, antisense RNA targeting ferrochelatase RNA, an agent for RNA silencing or RNA interference (RNAi) targeting ferrochelatase RNA, an agent for CRISPR/Cas9-mediated or Zinc-finger nuclease-mediated genetic ablation of ferrochelatase (FECH) DNA, an agent for anti-VEGF therapy, and combinations thereof. 
     
     
         10 . The method of  claim 1 , comprising administering to the compound to achieve an intravitreal concentration of from about 0.01 μM to about 500 μM. 
     
     
         11 . The method of  claim 1 , wherein the disease is cancer, and the cancer is selected from the group consisting of glioma, breast cancer, bladder cancer, colon cancer, and combinations thereof. 
     
     
         12 . The method of  claim 11 , further comprising treating the patient with photodynamic therapy (PDT). 
     
     
         13 . The method of  claim 1 , wherein compound is used to treat an ocular disease and is administered directly into the eye. 
     
     
         14 . The method of  claim 1 , wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The method of  claim 1 , wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         16 . The method of  claim 1 , wherein the compound is administered in a pharmaceutical composition and wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. 
     
     
         17 . The method of  claim 1 , further comprising the step of administering an anti-VEGF agent to the patient. 
     
     
         18 . The method of  claim 17 , wherein the anti-VEGF agent is selected from the group consisting of ranibizumab, bevacizumab, aflibercept, abicipar pegol, brolucizumab, faricimab, vorolanib, biosimilars to any of these VEGF agents, and combinations thereof. 
     
     
         19 . A method for treating a patient with malaria, the method comprising administering to the patient a therapeutically effective amount of a compound, wherein the compound is a triazolopyrimidinone, or a derivative thereof, or a pharmaceutically acceptable salt thereof. 
     
     
         20 . The method of  claim 19 , wherein the compound is of the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 R 1  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, or C 6 -C 10  aryl, or C 1 -C 6  alkylNR 4 R 5 , wherein each hydrogen atom in C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, or C 6 -C 10  aryl, is independently optionally substituted with fluoro, chloro, bromo, iodo, C 1 -C 6  alkyl, —OC 1 -C 6  alkyl, or C 6 -C 10  aryl; 
 each of R 2  and R 3  is independently selected from the group consisting of H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 6 -C 10  aryl, C 1 -C 6  alkyl-C 6 -C 10  aryl, and C 1 -C 6  alkylNR 6 R 7 , provided that at least one of R 2  and R 3  is not H, wherein each hydrogen atom in C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 6 -C 10  aryl, or C 1 -C 6  alkyl-C 6 -C 10  aryl, is independently optionally substituted with fluoro, chloro, bromo, iodo, —CO 2 R 8 , C 1 -C 6  alkyl, —OC 1 -C 6  alkyl, or C 6 -C 10  aryl; or R 2  and R 3 , when taken together with the carbon atoms to which they are attached, form a 5-7 membered carbocyclic ring; 
 each of R 4 , R 5 , R 6 , or R 7  is independently selected from the group consisting of H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, 5- to 7-membered monocyclic heteroaryl, C 6 -C 10  bicyclic heteroaryl, C 6 -C 10  aryl, and C 1 -C 6  alkyl-C 6 -C 10  aryl, wherein each hydrogen atom in C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, 5- to 7-membered monocyclic heteroaryl, C 6 -C 10  bicyclic heteroaryl, C 6 -C 10  aryl, or C 1 -C 6  alkyl-C 6 -C 10  aryl is independently optionally substituted with fluoro, chloro, bromo, iodo, —CO 2 R 8 , C 1 -C 6  alkyl, —OC 1 -C 6  alkyl, —OCF 3 , —CF 3  or C 6 -C 10  aryl; and 
 R 8  is H or C 1 -C 6  alkyl.